The estrogen receptor (ER) is a ligand activated mammalian transcription factor involved in the up and down regulation of gene expression. The natural hormone for the estrogen receptor is β-17-estradiol (E2) and closely related metabolites. Binding of estradiol to the estrogen receptor causes a dimerization of the receptor and the dimer in turn binds to estrogen response elements (ERE's) on DNA. The ER/DNA complex recruits other transcription factors responsible for the transcription of DNA downstream from the ERE into mRNA which is eventually translated into protein. Alternatively the interaction of ER with DNA may be indirect through the intermediacy of other transcription factors, most notably fos and jun. Since the expression of a large number of genes is regulated by the estrogen receptor and since the estrogen receptor is expressed in many cell types, modulation of the estrogen receptor through binding of either natural hormones or synthetic ER ligands can have profound effects on the physiology and pathophysiology of the organism.
Historically it has been believed there was only one estrogen receptor. However a second subtype (ER-β) has been discovered. While both the “classical” ER-α and the more recently discovered ER-β are widely distributed in different tissues, they nevertheless display markedly different cell type and tissue distributions. Therefore synthetic ligands which are either ER-α or ER-β selective may preserve the beneficial effects of estrogen while reducing the risk of undesirable side effects.
Estrogens are critical for sexual development in females. In addition, estrogens play an important role in maintaining bone density, regulation of blood lipid levels, and appear to have neuroprotective effects. Consequently decreased estrogen production in post-menopausal women is associated with a number of diseases such as osteoporosis, atherosclerosis, depression and cognitive disorders. Conversely certain types of proliferative diseases such as breast and uterine cancer and endometriosis are stimulated by estrogens and therefore antiestrogens (i.e., estrogen antagonists) have utility in the prevention and treatment of these types of disorders.
The efficacy of the natural estrogen, 17β-estradiol, for the treatment of various forms of depressive illness has also been demonstrated and it has been suggested that the anti-depressant activity of estrogen may be mediated via regulation of tryptophan hydroxylase activity and subsequent serotonin synthesis (See, e.g., Lu N Z, Shlaes T A, Cundlah C, Dziennis S E, Lyle R E, Bethea C L, “Ovarian steroid action on tryptophan hydroxylase protein and serotonin compared to localization of ovarian steroid receptors in midbrain of guinea pigs.” Endocrine 11:257-267, 1999). The pleiotropic nature of natural estrogen precludes its widespread, more chronic use due to the increased risk of proliferative effects on breast, uterine and ovarian tissues. The identification of the estrogen receptor, ERβ, has provided a means by which to identify more selective estrogen agents which have the desired anti-depressant activity in the absence of the proliferative effects which are mediated by ERα. Thus, it has been shown that therapeutic agents having ERβ-selectivity are potentially effective in the treatment of depression.
What is needed in the art are compounds that can produce the same positive responses as estrogen replacement therapy without the negative side effects. Also needed are estrogen-like compounds that exert selective effects on different tissues of the body.
Haroutounian et al, “Synthesis of novel nitro-substituted triaryl pyrazole derivatives as potential estrogen receptor ligands”, Molecules 2007, 12, 1259-1273, discloses the synthesis of certain nitro-substituted triaryl pyrazole derivatives and their binding affinity towards the estrogen receptor (ER) subtypes ERα and ERβ. Wiglenda and Gust, “Structure-activity relationship to understand the estrogen receptor-dependent gene activation of aryl- and alkyl-substituted 1H-imidazoles”, J. Med. Chem., 2007, 50, 1475-1484, discloses the synthesis of a series of C5-substituted 1,2,4-triaryl-1H-imidazoles, and the determination of their gene-activating properties on estrogen receptor alpha positive MCF-7 breast cancer cells, stably transfected with the plasmid EREetcluc (MCF-7-2a cells). WO2008/006626 discloses certain 5-membered heterocycles, preferably pyrroles, furans and thiophenes, substituted with three phenyl moieties, and further discloses that the compounds show antiproliferative effects and inhibitory effects on cyclooxygenases. Perumal et al, “Synthesis and antinociceptive activity of pyrazolyl isoxazolines and pyrazolyl isoxazoles”, Bioorg. Med. Chem. Lett., 2009, 19, 3370-3373, discloses the synthesis and antinociceptive activity of certain diphenyl pyrazolyl isoxazolines and pyrazolyl isoxazoles. WO 00/07996 discloses compounds having biological activity as estrogen receptor modulators. WO 2003/055860, JP 2006306755 and Org. Lett. Vol. 7 no. 11, 2005, pages 2157-2160 disclose pyrazole compounds having biological activity as heat shock protein 90 inhibitors. US 2007/0191336 discloses compounds having biological activity as nicotinic acetylcholine receptor modulators.
The compounds of the present invention are ligands for estrogen receptors and as such may be useful for treatment or prevention of a variety of conditions related to estrogen functioning.